A virus is composed of a nucleic acid molecule (DNA or RNA) and proteins or only composed of proteins (such as prion). Viruses can cause various infectious diseases. Common diseases caused by a virus include but are not limited to viral hepatitis type A, viral hepatitis type B, viral hepatitis C, influenza, herpes and acquired immunodeficiency syndrome (AIDS).
At present, antiviral drugs in clinical use take effects by inhibiting attachment and uncoating of the virus, virus gene replication and maturation or release, or by affecting the immune system of a host. Such antiviral drugs mainly include reverse transcriptase inhibitors, capsid protein assembly inhibitors and the like.
Hepatitis type B virus (HBV) is a common hepatophilic DNA viral pathogen. The virus may result in acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, liver cancer and the like.
Drugs for treating hepatitis type B include interferon and nucleoside analogues (such as lamivudine and adefovir dipivoxil). Among them, interferon interacts with a cell surface receptor to enable cells to produce antiviral proteins, thereby inhibiting the replication of hepatitis B virus. Disadvantages thereof are a relatively low effective response rate and need for long-term injection administration. The nucleoside analogues take effects mainly by inhibiting replication of viral polymerase (reverse transcriptase). The Disadvantage thereof is that the drugs need long lasting application which often results in viral mutation and leads to drug resistance.
Further, viral hepatitis type B can be treated with non-nucleoside analogues. A heteroaryl dihydropyrimidine compound (Bay41-4109) discovered by Deres et al. may prevent HBV virus replication by inhibiting viral capsid protein assembly (Science, 2003, 299, 893-896). The specific mechanism of action is as follows: the dihydropyrimidine compound induces defective assembly of core proteins, resulting in formation of unstable capsid proteins and acceleration of the degradation of the core proteins (Biochem. Pharmacol., 2003, 66, 2273-2279). Heteroaryl dihydropyrimidine compound HAP1 discovered by Zlotnick et al. (Proc. Natl. Acad. Sci., 2005, 102, 8138-8143) and a heteroaryl dihydropyrimidine compound (GLS4) reported by SUNSHINE LAKE PHARMA CO., LTD. (Antimicrob. Agents Chemother., 2013, 57, 5344-5354; WO2015078391, US2016206616 and WO2015144093) also have anti-HBV activity.
Although the above compounds exhibit some degree of viral suppression, the antiviral activity thereof is still not satisfied. Moreover, some compounds also exhibit significant toxic effects (e.g., GLS4 exhibits significant hERG cardiotoxicity).